MX2014001759A - Use of propanoic acid 3-[(2,5-dimethylphenyl)carbamoyl]-2-(pipera zine-1-yl) and its chemical derivatives as inhibitors of neuraminidase of human and animal influenza virus. - Google Patents

Abstract

The present invention is related to the use of propanoic acid 3-[(2,5-dimethylphenyl)carbamoyl]-2-(piperazine-1-yl) for preparing a pharmaceutical composition useful in the treatment of viral influenza. The propanoic acid 3-[(2,5-dimethylphenyl)carbamoyl]-2-(piperazine-1-yl) has the property of inhibiting the enzymatic activity of the neuraminidase enzyme.

Description

USE OF PROPANOIC ACID 3-r (2.5-DIMETHYLPHENYCCARBAMOILl-2- (PIPERAZIN-1-IL) AND ITS CHEMICAL DERIVATIVES AS INHIBITORS OF NEURAMINIDASE OF THE HUMAN AND ANIMAL INFLUENZA VIRUS Field of the invention The present invention pertains to the technical field of drugs against viral agents. More particularly, it belongs to the technical field of drugs against the influenza virus. More particularly, it belongs to the technical field of drugs inhibiting the neuraminidase enzyme of the influenza virus.

State of the art Influenza or influenza is a disease that consists of acute viral infection of the upper respiratory tract. Influenza causes seasonal respiratory epidemics every year mainly in autumn and winter in the world, resulting in 3 to 5 million patients per year, causing between 250 000 to 500 000 deaths. This disease is caused by a virus that belongs to the Orthomyxoviridae family, which comprises 5 genera: Influenza virus A, Influenza virus B, Influenza virus C, Thogotovirus and Isavirus.

Three genera of Influenza virus are known: Influenza virus A, Influenza virus B and Influenza virus C, this classification is given according to the three proteins expressed in the plasma membrane, hemagglutinin (HA), neuraminidase (NA), and the transmembrane M2 protein which forms channels in the lipid envelope. In addition, there are matrix protein antigens (M) for each genus, important for the assembly and maintenance of the viral structure, other proteins that are part of the replication complex (PA, PB1 and PB2), and the nucleoproteins (NP) that make up and protect the i viral genome The antigenic properties of the Influenza A virus are determined by the envelope glycoproteins HA and NA.

Commonly, the treatment of influenza is through antivirals, which are divided into two classes: 1) adamantanes (amantadine and remantadine) which are inhibitors of matrix protein 2 (M2), and 2) inhibitors of neuraminidase ( Oseltamivir and Zanamivir). However, many influenza viruses develop resistance to antiviral drugs, which limits the effectiveness of the treatment.

In this sense, the patent application WO2013106937A1 describes 2,3-fluorinated glycosides that inhibit the enzyme neuraminidase, which is useful for the treatment of viral influenza.

On the other hand. Patent application WO2013070118A1 describes a carboxylic acid 4,5-diamino-3-alkyloxy-cyclohex-1-ene, esters thereof, or pharmaceutically acceptable salts, which inhibits the activity of neuraminidase of influenza virus, as well as pharmaceutical compositions and production methods thereof.

Likewise, the patent application CN102204914A describes the use of the salts 4-alkyl-6-aryl-5-acetyl-1,3-thiazine, 4-alkyl-6-aryl-5-acetyl-2-amino-1, 3-thiazine, or 4-a Iq ui-6-a ri I-5-acetyl-2-amido-1,3-thiazine to prepare a neuraminidase inhibitor of influenza viruses.

Additionally, the patent application W02009087062A2 describes polymorphic forms of Oseltamivir phosphate, especially the acid ethyl phosphate (3R, 4R, 5S) -5-amino-4-acetylamino-3- (1-ethyl-propoxy) -cyclohex- 1-ene-carboxylic acid, which are potent inhibitors of the viral nueraminidase.

Brief description of the figures Figure 1 is the formula of the propanoic acid compound 3 - [(2,5-dlmethylphenyl) carbamoyl] -2- (piperazin-1 -II).

Figure 2 is a graph relating to the inhibition of the enzyme neuraminidase of avian (empty circles) and human origin (filled circles).

Best method of carrying out the invention The pharmaceutical composition containing the propanoic acid 3 - [(2, 5-di metí If eni I) carbamoyl] -2- (piperazin-1-yl) (figure 1) of the present invention can be prepared according to known methods in the state of the technique. The present composition comprises propanoic acid 3 - [(2,5-dimethylphenyl) carbamoyl] -2- (piperazin-1-yl), together with one or more pharmaceutically acceptable carriers and / or excipients.

The available haulers are not only inorganic carriers, but also organic haulers. Thus, for example, they can be used as carriers for tablets, coated tablets, dragees, and hard gelatin capsules, lactose, starch or derivatives thereof, talc, stearic acid or salts thereof. Carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and liquid and solid polyols. Carriers for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar. Carriers for solutions for injections are, for example, water, alcohols, polyols, glycerol and vegetable oils. The carriers for suppositories are, for example, natural or hardened oils, waxes, fats and liquid or semi-liquid polyols. Carriers for topical preparations are glycerides, synthetic and semi-synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

As pharmaceutical adjuvants agents should be considered stabilizers, wetting agents and emulsifiers, agents that improve the consistency, agents that improve the flavor, salts to vary the osmotic pressure, pH buffering agents, solubilizers, dyes and masking agents and antioxidants.

The dosage of the compound can vary within wide limits depending on the age and condition of the individual, and mode of administration. For adult patients a daily dose of about 1 to 1000 mg, especially about 1 to 100 mg, can be considered. Depending on the severity of the disease and the precise pharmacokinetic profile the compound can be administered with one or several daily doses, for example 1 to 3 unit doses.

The pharmaceutical preparations conveniently contain about 1-500 mg, preferably 1-100 mg, of the crystalline form of the compound.

The composition of the present invention can be administered by oral (including buccal and sublingual), intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, and mucosal routes. The route of administration will depend on the composition of a particular therapeutic preparation of the invention.

When propanoic acid 3 - [(2,5-dimethylphenyl) carbamoyl] -2- (piperazin-1-yl) is formulated together with a pharmaceutically acceptable excipient, any excipient can be used, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives.

The pharmaceutical composition can take any available form, and include for example tablets, capsules, solutions, suspensions, powders, granules and aerosols.

Tablets for oral use may contain propanoic acid 3 - [(2,5-dimethylphenyl) carbamoyl] -2- (piperazin-1-yl) mixed with pharmaceutically acceptable excipients, such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Available inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are available as disintegrating agents. The binding agents may include starch and gelatin, while the lubricating agents, if present, will generally be magnesium stearate, stearic acid, or talc.

Capsules for oral use include gelatin hard capsules, in which propanoic acid 3 - [(2,5-d.methylphenyl) carbamoyl] -2- (piperazin-1-yl) is mixed with a solid diluent, and soft gelatine capsules, wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous, and intravenous use, propanoic acid 3 - [(2,5-di methyl Ife or I) carbamoyl] -2- (piperazin-1-yl) will generally be provided in sterile, buffered aqueous solutions or suspensions at an appropriate pH and isotonicity.

The amount of propanoic acid 3 - [(2,5-dimethylphenyl) carbamoyl] -2- (piperazin-1-yl) administered can vary extensively according to the dose unit employed, the treatment period, age, weight, kind of treatment attached, and sex of the patient to be treated.

It should be understood that the methyl groups of the formula of Figure 1 can be optionally substituted by halogens, such as -chloro, -iodo, -fluor, or -bromo.

The invention will now be described with reference to specific examples. They are merely for illustrative purposes: they do not in any way attempt to limit in any way the scope of the described invention. Said examples up to now constitute the best method currently contemplated for the practice of the invention. Example 1. Cell culture To obtain the viral inocula, the MDCK cell line (Madin-Darby canine kidney) was used, which was cultured in Eagle's minimal essential medium (E-MEM, Sigma) supplemented with 10% fetal bovine serum (Hyclone). 37 ° C and 5% CO2. Example 2. Virus culture Human strains A / PR / 8/34 (H1N1) and A / Chicken / Mexico / 232/94 / CPA avian influenza A virus were used, which were inoculated in MDCK cells with confluence of 70-80%. The supernatants of the infected cultures were obtained at 96 h post-infection and clarified by low speed centrifugation and stored at -70 ° C until use.

Example 3. Determination of neuraminidase activity The activity of the NA protein of the virus was determined by incubating the supernatants of the cultures infected with bovine serum fetuin (Sigma) as a substrate. The mixture of virus, substrate, buffer (0.1 M sodium phosphate, pH 5.5) was made in a final volume of 200 pl. The mixture was incubated for 30 minutes at 37 ° C and the reaction was stopped by boiling for 2 minutes. The neuraminic acid liberated by the enzyme was quantified by the modified thiobarbituric acid method, which consists of the oxidation of soluble neuraminic acid by periodic acid and its subsequent combination with thiobarbituric acid to give a colorful complex whose maximum absorbance is recorded at 550 nm. The activity was reported in residual activity of the enzyme neuraminidase in percentage with respect to the activity of the enzyme without inhibitor.

Claims (2)

1. The use of propanoic acid 3 - [(2,5-dimethylphenyl) carbamoyl] -2- (piperazin-1-yl) to prepare a pharmaceutical composition useful for the treatment of viral influenza.

2. A pharmaceutical composition for the treatment of viral influenza, characterized in that it comprises: i) propanoic acid 3 - [(2,5-dimethylphenyl) carbamoyl] -2- (piperazin-1-yl), and ii) a pharmaceutically acceptable carrier.